Autoimmune Disease in the U.S.- Part 3 in 6-Part Series

What are the mechanisms and mediators involved in autoimmunity? Intestinal permeability promotes autoimmunity. Gluten sensitivity and autoimmunity connection.

Main points of this issue:

  • Intestinal permeability promotes autoimmunity
  • Intestinal permeability occurs when the tight junctions of the intestinal mucosa are compromised
  • Intestinal permeability may be a necessary condition for the development of autoimmunity
  • Malabsorption is common in intestinal permeability
  • Autoimmunity itself tends to cause further intestinal permeability
  • Gluten sensitivity has been found to initiate intestinal permeability
  • Celiac disease (CD) is an autoimmune disease resulting from extreme gluten sensitivity
  • Most cases (87.5%) of CD remain undiagnosed
  • CD significantly increases risk of developing other autoimmune diseases
  • Not all cases of gluten sensitivity result in Celiac disease (CD)
  • 2/3 of people with gluten sensitivity do not have GI enteropathy
  • Most gluten sensitivity affects the brain, not the GI tract
  • Gluten sensitivity may manifest in a number of neurological deficits
  • Gluten sensitivity has been linked to several autoimmune diseases, in addition to CD

Intestinal permeability promotes autoimmunity

We know there are links of intestinal permeability to autoimmunity. When a person develops intestinal permeability, there is a whole list of health problems that take place. Most people in the conventional world don’t know about leaky gut syndrome or intestinal permeability yet. This will change shortly because drug companies are now working on a drug to treat intestinal permeability. Once they develop a drug, everyone will know about it.

What is intestinal permeability (or “leaky gut” syndrome)?

The lining of the gastrointestinal (GI) tract is made up of small epithelial cells that lie side-by-side each other forming tight junctions. These cells act as a barrier between the interior of the body (blood/circulatory system)and the exterior of the body (the GI tube). There are two primary functions of the intestinal lining of the GI tract: the first is to absorb small, micromolecules, such as digested food particles, which are used as fuel sources for the body. These micronutrients are absorbed directly into the epithelial cells. The second, is to prevent the absorption of larger macromolecules which should not penetrate through the intestinal barrier. When tight junctions of the intestinal mucosa are compromised, they become widened and permeable to large undigested compounds, toxins and bacteria, known as “leaky gut”. The larger compounds of absorbed yet undigested proteins are reacted against by the underlying intestinal immune system. This reaction then promotes exaggerated immune responsiveness and intestinal inflammation. This creates a vicious cycle of further intestinal inflammation and increased intestinal permeability.

Paper after paper in the literature is showing that intestinal permeability promotes autoimmune reactions, flare-ups and overzealousness of the immune system:

“A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism.”1

“When the finely tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur.”2

“It is now apparent that tight junctions are dynamic structures that are involved in developmental, physiological, and pathological processes. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of several diseases, particularly autoimmune diseases.”3

The literature shows a close connection between increased food sensitivities and intestinal permeability:

“Intestinal permeability is increased in patients with food allergy, suggesting that the uptake of food antigens is elevated in food-allergic patients.”4

One of the things researchers are finding is once these tight junction proteins get compromised, there is such immune zealousness and activation, this whole immune self-tolerance is lost, resulting in autoimmunity:

“In all cases, increased permeability appears to precede disease and causes an abnormality in antigen delivery that triggers the multiorgan process leading to the autoimmune response.”5

“Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. When the finely-tuned trafficking of macromolecules is dysregulated in individuals, both intestinal and extraintestinal autoimmune disorders can occur.”6

A recent article published in a well-respected medical journal hypothesized that intestinal permeability is a necessary condition for the development of autoimmunity:

“There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases. Therefore, we hypothesize that loss of intestinal barrier function is necessary to develop autoimmunity Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms.”7

Malabsorption is Common in Leaky Gut

The other consequence of intestinal permeability is malabsorption of nurients. Many of these leaky gut patients get malabsorption because the inflammation that occurs from the penetration of peptides causes mucus formation. The mucus makes it difficult for small micronutrients to penetrate the intestinal epithelial cells. The larger molecules are able to penetrate because of their greater mass. So you get leaky gut with malabsorption issues. This becomes a serious problem.

Autoimmunity Itself Tends to Cause Further Intestinal Permeability

We now know autoimmunity also leads to leaky gut. Cytokine explosions from autoimmunity immediately destroy the tight junctions of the intestinal barrier. As the autoimmunity flares up, these patients get increased intestinal permeability. Most people who have autoimmunity feel better until they get a flare up, then they get worse. Whenever they get flare-ups, they are getting some degree of intestinal permeability. The autoimmunity itself tends to perpetuate the leaky gut syndrome and this becomes a vicious cycle.

What are Some of the Mediators and Modulating Factors that Contribute to Autoimmunity?

  • Gluten sensitivity

Gluten is the protein found in wheat which can be broken down into gliadin and glutenin. Gliadin is the portion of gluten that initiates the immune response in gluten sensitivity. However, recent research indicates that gluten sensitive individuals may react to glutenin as well.

Immune responses to gliadin have been found to initiate intestinal permeability via upregulation of zonulin:

“Gliadin and its peptides interact with the intestinal epithelium increasing intestinal permeability through the release of zonulin that, in turn, enables paracellular translocation of gliadin and its subsequent interaction with macrophages within the intestinal submucosa (in CD patients).”8

“Therefore, understanding the interactions between the upregulation of zonulin, increased intestinal permeability, and the development of autoimmune diseases may lead to novel preventative and possibly therapeutic strategies for type 1 diabetes.”9

Celiac Disease: An autoimmune disease resulting from extreme gluten sensitivity

We know that gluten sensitivity has major impacts on health. One of the most extreme cases of gluten sensitivity results in an autoimmune disease called Celiac disease. In Celiac disease (CD), the immune system’s response to gluten exposure results in chronic inflammation and destruction of the GI tract. This is the only known autoimmune disease which results directly from exposure to a food whose progression can be stopped by avoidance to exposure that food.

Most cases of CD remain undiagnosed

It is estimated that only the patients with clinically overt celiac disease (12.5%) get diagnosed. This is only the “tip of the iceberg”. The other 87.5% of patients with CD remain undiagnosed with “silent celiac disease”. These patients are asymptomatic but have positive test results. “The current ratio of clinically diagnosed to undetected cases that is “the size of the iceberg” is approximately 1 to 8.” 10

“For every symptomatic patient with CD there are eight patients with CD and no GI symptoms.” 11

Celiac Disease (CD) Significantly Increases Risk of Developing Other Autoimmune Disease

The damage to the GI tract in CD can be devastating. However, the GI tract is not the only tissue that may be the target of immune destruction. When a person has full-blown celiac disease type reactions, any other tissue of the body can be attacked.

“Associated autoimmune antibodies are frequent in CD and their first-degree relatives, spanning anti-endocrine, anti-gastrointestinal, anti-nuclear, anti-cytoskeleton and anti-neurological antibodies.”

“More specifically, in numerous studies, antibodies against thyroid and the endocrine pancreas, anti-gastric and liver, anti-nuclear constituents, anti-reticulin, actin, smooth muscle, calreticulin, desmin, collagens and bone, anti-brain, ganglioside, neuronal and blood vessel were described in sera of the patients.”12

Gluten sensitivity vs. Celiac disease

Not all cases of gluten sensitivity result in celiac disease (CD). There are many forms of gluten sensitivity that are unrelated to CD. Gluten sensitivity is defined by having an immune response to gluten. To have celiac disease, you have to have other criteria. With enteropathy (gastrointestinal disease), you need the HLA-DQ2 or DQ8 genes and gliadin antibodies present in the blood. Then you need either positive serum transglutaminase or positive biopsy results, depending on the source.

There are still many doctors that are fixated on the celiac-disease model which is focused on intestinal manifestation of gluten sensitivity. There are other cases of enteropathy (GI disease) associated with gluten without the specific genotype. This is known as “non-celiac gluten enteropathy”.

Most people with gluten sensitivity do not have gastrointestinal symptoms

The other mistake that many doctors make is they associate gluten sensitivity with disease of the intestinal tract. 2/3 of people with gluten sensitivity do not have gastrointestinal symptoms. What other organs does it affect? Once a person has gluten sensitivity without enteropathy, it can destroy any tissue. The most vulnerable tissue is the brain. Most gluten sensitivity affects the brain, not the GI tract.

“Patients with an enteropathy (disease of the intestinal tract) represent only a third of patients with neurological manifestations and gluten sensitivity.”13

Gluten sensitivity may manifest in a number of neurological deficits, depending on what part of the brain or nervous system is affected, including numbness and tingling, ataxia (balance problems), migraines, attention-deficit problems or ADHD, “brain fog”, and cognitive deficits.14,15 Gluten sensitivity is now being found to be involved in the pathological processes of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, supranuclear palsy, and Huntington’s disease:

“In this review, we discuss the molecular mechanisms of the transglutaminases involved in the pathological processes responsible for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, supranuclear palsy, Huntington’s disease, and other recently identified polyglutamine diseases”16

Gluten Sensitivity and Autoimmune Disease:

  • Type I diabetes

“These and recent data show that exposure to dietary gluten in offspring of mothers and fathers with type 1 diabetes very early in life is associated with an increased risk of developing islet cell antibodies. These data also suggest that removal of dietary gluten should be tested as early as possible”17

“The frequency of CD in DM (diabetes mellitus) type 1 was 9.71%” 18

  • Hashimoto’s Autoimmune Thyroid

“Our findings demonstrated an increased prevalence of thyroid disorders with CD.” 19

A study of 100 subjects with autoimmune thyroid disease monitored their response after a gluten-free diet or a gluten-containing diet to evaluate the effect of dietary habits on their thyroid function.

“Results: The abnormal thyroid serological markers became undetectable 6 months after beginning a gluten-free diet

Conclusion: This study indicates that a gluten-free diet may have profound impacts on patients with autoimmune thyroid disease and gluten withdrawal may single-handedly reverse the abnormality, although it does not cure the condition.” 20

This study confirmed that removing gluten from the diet alone had significant impacts on serum markers of autoimmune thyroid disease.

  • Rheumatoid Arthritis

“Increased levels of antigliadin antibodies were found in 37% of all RA patients.”21

These studies support the correlation between gluten sensitivity (and especially celiac disease) and increased risk of various autoimmune diseases.

Content provided by Datis Kharrazian, D.C., Autoimmune Regulation of the Nitric Oxide and Glutathione Systems, 11/4/10

In part 4 of this 6-part series, we answer the following questions:

  • What role do chronic bacterial and viral infections play in autoimmunity?
  • What role do environmental toxins play?
  • The role of the glutathione and nitric oxide synthase (NOS) systems and development of autoimmunity.

Continue to part 4 of series

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21. Gliadin immune reactivity in patients with RA. Clin Exp Rheumatol. 1995 Sep-Oct;13(5): 603-7